Background Abuse of opioids is an important problem for the Veterans Health Administration, with serious medical, psychiatric, social, and economic consequences. Given the increasing prevalence of fatal overdose and other negative health outcomes associated with opioid abuse, new and innovative treatments are urgently needed. Melatonin is a hormone and neurotransmitter produced primarily by the pineal gland, which plays a role in establishing daily and seasonal rhythms. Exogenous melatonin decreases both opioid tolerance and the severity of withdrawal, which may decrease opioid-reinforced behavior. It also attenuates the expression of morphine-induced conditioned place preference and decreases cocaine-reinforced behavior. Ramelteon and agomelatine are potent agonists at melatonin receptors that are structurally related to melatonin and approved for human use. Rationale This project will evaluate clinically available melatonin agonists for their effects on opioid actions, self-administration, and disruption of the sleep-wake cycle. Interruption of the light-dark cycle in rats that increases oral morphine intake is associated with a decreased plasma concentration of melatonin. This finding, combined with observations of diminished morphine-induced conditioned-place preference after administration of exogenous melatonin, indicate that melatonin agonists may be useful as treatments to prevent opioid use in humans. Recently, we found that pretreatment with the serotonin-2C receptor (5-HT2CR) agonist lorcaserin increases the positive subjective effects of cocaine, suggesting a role for antagonists of this subtype. Agomelatine but not ramelteon acts as an antagonist at the 5-HT2CR. This property, as well as melatonin agonist activity, may decrease the reinforcing effects of opioids. Antidepressant effects of agomelatine may also be beneficial in patients with substance abuse disorders. A preliminary open-label study noted decreased craving in patients with substance abuse disorders treated with agomelatine. To initiate evaluation as potential treatments for opioid-use disorder, this project will assess the effects of melatonin agonists with or without compounds that modify the 5-HT2CR using a rat model of opioid-reinforced behavior. Specific Aims: 1. Measure Effects of Ramelteon on Sleep, Tolerance-Dependence, and Morphine Self-Administration; 2. Evaluate Agomelatine, A Combined Melatonin Agonist and 5-HT2CR Antagonist; and 3. Assess Combined Effects of Ramelteon and Lorcaserin, a 5-HT2CR Agonist. Methods Outbred Wistar rats will be maintained on a reversed light-dark cycle, with food- and morphine- self- administration sessions conducted during darkness in the daytime. Rats will be allowed to establish opioid dependence by self-administration of morphine. The duration and continuity of sleep and awake behaviors will be recorded noninvasively each day when rats are returned to home cages. As morphine is withdrawn during a one-week extinction period, melatonin agonists will be delivered either by around-the-clock dosing or once- daily injection one hour prior to the onset of darkness (active periods). Effects on non-reinforced responding will be recorded during extinction and reinstatement. Melatonin agonist treatments will be continued as rats are allowed to reacquire self-administration of morphine. In other animals that receive fixed, noncontingent doses of morphine and melatonin agonists, the entire sleep- wake cycle will be recorded noninvasively; with subsequent evaluations for opioid tolerance, precipitated withdrawal, and immobility during forced swimming. Antioxidant- and inflammatory- mediators will be measured in brain tissue.